Phenylacetylglycine

Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.

Numerous studies have investigated metabolite alterations resulting from pharmacological treatment in depression models although few quantitative studies explored metabolites exhibiting constant alterations. This study aimed to identify consistently dysregulated metabolites across such studies using a knowledgebase-driven approach. This study was based on 157 studies that identified an assembly of 2757 differential metabolites in the brain, blood, urine, liver, and feces samples of depression models with pharmacological medication. The use of a vote-counting approach to identify consistently upregulated and downregulated metabolites showed that serotonin, dopamine, norepinephrine, gamma-aminobutyric acid, anandamide, tryptophan, hypoxanthine, and 3-methoxytyramine were upregulated in the brain, while quinolinic acid, glutamic acid, 5-hydroxyindoleacetic acid, myo-inositol, lactic acid, and the kynurenine/tryptophan ratio were downregulated. Circulating levels of trimethylamine N-oxide, isoleucine, leucine, tryptophan, creatine, serotonin, valine, betaine, and low-density lipoprotein were elevated. In contrast, levels of alpha-D-glucose, lactic acid, N-acetyl glycoprotein, glutamine, beta-D-glucose, corticosterone, alanine, phenylacetylglycine, glycine, high-density lipoprotein, arachidonic acid, myo-inositol, allantoin, and taurine were decreased. Moreover, 12 metabolites in urine and nine metabolites in the liver were dysregulated after treatment. Pharmacological treatment also increased fecal levels of butyric acid, acetic acid, propionic acid, and isovaleric acid. Collectively, metabolite disturbances induced by depression were reversed by pharmacological treatment. Pharmacological medication reversed the reduction of brain neurotransmitters caused by depression, modulated disturbance of the tryptophan-kynurenine pathway and inflammatory activation, and alleviated abnormalities of amino acid metabolism, energy metabolism, lipid metabolism, and gut microbiota-derived metabolites.

Background: Myocardial ischemia/reperfusion (I/R) injury is closely related to cardiomyocyte apoptosis. Stimulating β2 adrenergic receptor (β2AR) can effectively combat cardiomyocyte apoptosis. Previous studies demonstrate that the gut microbial metabolite phenylacetylglycine (PAGly) can stimulate β2AR. However, the effect of PAGly on myocardial I/R injury remains unknown. Methods: The hypoxia/reoxygenation (H/R) model was established using the neonatal mouse cardiomyocytes (NMCMs). Different doses of PAGly were used to treat NMCMs, and apoptosis was detected by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. Additionally, the level of cyclic adenosine monophosphate (cAMP) was examined by using a cAMP detection kit. Mouse model of myocardial I/R injury was established in C57BL/6 mice, and different doses of phenylacetic acid were administrated intraperitoneally. Apoptosis of myocardial cells was detected by TUNEL and α-actin staining. The area at risk and the infarct areas were identified by 2,3,5-triphenyltetrazolium chloride (TTC) and Evans blue staining. Western blotting was used to measure the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (p-PI3K), total Akt (t-Akt), phosphorylated Akt (p-AKT), Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved caspase-3. Results: PAGly significantly suppressed H/R injury-induced apoptosis in NMCMs and inhibited apoptosis in myocardial I/R injured mice in vivo. We verified that PAGly activated the anti-apoptotic Gαi/PI3K/AKT signaling cascade in NMCMs via stimulating β2AR signaling. Continuous administration of PAGly at an appropriate dose could inhibit apoptosis and reduce the infarct size resulting from I/R injury in mice. However, high-dose PAGly treatment was associated with a higher mortality rate. Moreover, we demonstrated that Aspirin reduced the infarct size and the high mortality caused by high doses of PAGly in I/R injured mice. Conclusions: These findings suggest that treatment with the gut microbial metabolite PAGly could suppress cardiomyocyte apoptosis caused by myocardial I/R injury and reduce the infarct size, which provides a novel therapeutic strategy for patients with myocardial infarction.